School Immunity and Infection, University of Birmingham, Birmingham, UK.
Leuk Res. 2012 Nov;36(11):1434-7. doi: 10.1016/j.leukres.2012.07.013. Epub 2012 Aug 5.
The PRH/Hhex transcription factor represses multiple genes in the VEGF signalling pathway (VSP) to inhibit myeloid cell survival. Protein kinase CK2 phosphorylates PRH and counteracts the inhibitory effect of this protein on cell survival by blocking the repression of VSP genes. Here we show that the BCR-ABL/Src kinase inhibitor dasatinib decreases PRH phosphorylation and increases PRH-dependent repression of Vegf and Vegfr-1. Moreover in the absence of PRH, dasatinib does not inhibit cell survival as effectively as in PRH expressing cells. Thus the re-establishment of gene control by PRH is in part responsible for the therapeutic effects of dasatinib.
PRH/Hhex 转录因子抑制 VEGF 信号通路 (VSP) 中的多个基因以抑制髓样细胞存活。蛋白激酶 CK2 磷酸化 PRH，并通过阻断 VSP 基因的抑制作用来抵消该蛋白对细胞存活的抑制作用。在这里，我们表明 BCR-ABL/Src 激酶抑制剂 dasatinib 降低了 PRH 的磷酸化水平，并增加了 PRH 对 Vegf 和 Vegfr-1 的依赖性抑制。此外，在没有 PRH 的情况下，dasatinib 抑制细胞存活的效果不如在表达 PRH 的细胞中那么有效。因此，PRH 重新建立基因控制部分解释了 dasatinib 的治疗效果。
